Genetic Variant IKZF2:p.Asp318Glu (chr2-213007987-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001387220.1(IKZF2):c.954C>A(p.Asp318Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

IKZF2
NM_001387220.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Publications

0 publications found

Variant links:

Genes affected

IKZF2 (HGNC:13177): (IKAROS family zinc finger 2) This gene encodes a member of the Ikaros family of zinc-finger proteins. Three members of this protein family (Ikaros, Aiolos and Helios) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. This protein forms homo- or hetero-dimers with other Ikaros family members, and is thought to function predominantly in early hematopoietic development. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

IKZF2 Gene-Disease associations (from GenCC):

HELIOS deficiency
Inheritance: SD, AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
hearing loss disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
immunodeficiency disease
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

IKZF2 links:

ENSG00000273118 (HGNC:):

ENSG00000273118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF2	NM_001387220.1 link	c.954C>A	p.Asp318Glu	missense_variant	Exon 9 of 9	ENST00000434687.6	NP_001374149.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF2	ENST00000434687.6 link	c.954C>A	p.Asp318Glu	missense_variant	Exon 9 of 9	5	NM_001387220.1	ENSP00000412869.1		Q9UKS7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461404

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111764

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.954C>A (p.D318E) alteration is located in exon 8 (coding exon 7) of the IKZF2 gene. This alteration results from a C to A substitution at nucleotide position 954, causing the aspartic acid (D) at amino acid position 318 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.0075

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

.;.;.;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.51

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

.;.;.;M;.

PhyloP100

5.8

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.9

.;.;D;D;D

REVEL

Benign

0.26

Sift

Benign

0.20

.;.;T;T;T

Sift4G

Benign

0.086

T;T;T;T;T

Polyphen

0.99, 0.78

.;.;.;D;P

Vest4

0.55

MutPred

0.55

.;.;.;Loss of catalytic residue at D318 (P = 0.0168);.;

MVP

0.46

MPC

0.86

ClinPred

0.96

GERP RS

6.0

Varity_R

0.44

gMVP

0.60

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-213007987-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over